There are many types and causes of sensorineural hearing loss, i.e., hearing loss associated with damage to the inner ear, rather than say, a punctured ear drum. You can lose hearing from exposure to loud noises, medications with toxic side effects, or simply having been born with congenital hearing loss. Aging is a major risk factor too.

While two percent of adults ages 45 to 53 have disabling hearing loss, according to the National Institute on Deafness and Other Communication Disorders, that rate jumps to 25% by ages 65 to 75 and fully half of those 75 and older.

But if the disorders are varied and, in some cases common, the treatments are not. There are at present no FDA approved treatments for sensorineural hearing loss, save hearing aids and cochlear implants.

One reason for that is the inner ear is difficult to access, particularly the cochlea, which transduces sound waves to nerve impulses, says Anthony Mikulec, MD, an otolaryngologist and professor at St. Louis University in the department of otolaryngology.

“Up until now, that has been a black box. If you opened up the cochlea,” he notes, “that often lead to deafness.” For that reason, cochlear implants, as revolutionary as they have been for treating deafness, are generally used for treating those who are already deaf, Mikulec adds. “What we’d really like to do is prevent deafness to begin with and prevent hearing loss with aging.”

Over the last few years, more than 20 otology companies have emerged with hopes of doing just that. Their therapies and delivery techniques are varied, but they all aim to treat disease of the inner ear in ways that have never been done before.

One of the first, San Diego-based Otonomy has taken a gelatinous version of existing steroid treatments for Meniere’s disease to Phase III clinical trials, while Seattle’s Sound Pharmaceuticals is moving a small molecule for the treatment of acute noise induced hearing loss to Phase II trials. Decibel Therapeutics is doing preclinical work using gene therapy to treat monogenic hearing loss, while several companies, including Frequency Therapeutics and Audion, are exploring what Mikulec calls the Holy Grail—regenerating hair cells in the cochlea. That could mean truly restoring lost hearing and will be an order of magnitude more difficult that tackling tinnitus. But, according to Mikulec, “these are serious efforts and they didn’t exist 10 years ago.”

Frequency recently reported results from a Phase 1/2 clinical trial of 23 patients with stable sensorineural hearing loss, which showed that treatment with its small molecule therapy, FX-322, produced statistically significant and clinically meaningful improvements in key measures of hearing loss, including clarity of sound. In multiple patients, improvements in word recognition and words-in-noise, as well as pure tone thresholds at 8000Hz, were observed in FX-322 treated subjects. The company this month initiated dosing in a Phase 2a trial to further establish the hearing signal seen in the Phase 1/2 study and to also evaluate dosing regimens and patient populations. The FDA recently granted FX-322 Fast Track designation. Earlier this year, Frequency licensed ex-US rights to FX-322 to Astellas, a deal valued at up to $625 million, and in October completed an $84 million IPO.

 

Taking a dual approach

Founded in 2008 and with one medication—Otiprio, for pediatric ear infections—already on the market, Otonomy is one of the best established of this wave of otology startups, says Mikulec. “They’re kind of the granddaddy of them all,” he continues. “They’ve diligently done the clinical trials over the years.”

The most advanced program in Otonomy’s pipeline is a treatment for Ménière’s disease, which was the condition that led to the company’s founding, according to CEO David Weber. “One of our founders, Jay Lichter, is a partner at Avalon Ventures,” Weber says. “He had an attack of vertigo while he was in the car.” Ménière’s disease is an inner ear disorder that can include hearing loss and tinnitus, but it is the bouts of dizziness that are most extreme, lasting hours, causing vomiting and making standing impossible. “They call them drop attacks,” Weber explains.

Lichter endured what has been one of the only available treatments for severe Ménière’s, the injection of an aqueous solution of steroids into the middle ear through the eardrum. It’s a significant amount of liquid that is injected, Weber says, which is physically and aurally uncomfortable. “Jay describes it as the sound of a freight train in your ear,” Weber says.

The patient also has to lay with their head still as long as possible after the injection to ensure the medication has time to absorb—if they move or even swallow, the “liquid will drain out the eustachian tube,” and the medication stops absorbing.

This highlights the double difficulty in developing treatments for diseases of the inner ear, continues Weber. Not only must you have an efficacious medicine, you need a means of getting it to where it needs to go, so “from the beginning we took a dual approach of developing both treatments and means of administrating treatments,” states Weber.

Otonomy has developed a thermosentive gel that can be injected through the eardrum, becoming viscous once in the middle ear allowing medications more time to absorb and requiring less fluid volume than aqueous solutions. In the case of Ménière’s, the medication is the steroid dexamethasone in a formulation Otonomy calls Otividex. The technology is already being used for Otonomy’s Otiprio medication, which uses the gel to deliver the antibiotic ciprofloxacin.

Other programs in Otonomy’s pipeline include OTO-413, a brain-derived neurotrophic factor, or BDNF, delivered into the middle ear for sustained release through Otonomy’s gel and aimed at repairing cochlear synapses damaged by noise or toxic chemicals, according to Weber. The company has a Phase I/II clinical trial scheduled for the latter half of 2020. OTO-313 again uses Otonomy’s delivery method to inject gacyclidine, a N-Methyl-D-Aspartate (NMDA) receptor antagonist, in hopes of quelling excitotoxicity and treating tinnitus, with a Phase I/II trial scheduled to bring results in the first half of 2020.

As for Otividex, Otonomy expects results from a Phase III clinical trial in early 2020.

“In the next couple years, that’ll be pretty the standard of care for Ménière’s syndrome,” Mikulec says of Otividex, assuming the trial shows positive results—the company did have to re-evaluate when the treatment failed to meet the endpoints of a Phase III trial in 2017.

 

Hearing decibels

Decibel Therapeutics has an origin story that’s similar to Otonomy’s, though a different approach, according to COO Paula Cobb. It started with one of the partners at Third Rock Ventures dealing with tinnitus. He asked, “Why are there no medicines for the inner ear, yet? Every other part of the body has medicines that have been developed for it.” Cobb says, “You look at hearing and balance, and there’s just really so little.” Third Rock saw an opportunity and formed Decibel in 2015.

“A really important decision that we made early on at Decibel was that we were going to be modality agnostic,” Cobb says of the company’s approach. They have focused on identifying different pathologies of the inner ear and then developed the modality of treatment and route of administration from there, leading to a diverse pipeline.

The company’s lead program is a small molecule—DB-020—injected into the middle ear and designed to protect hair cells in the cochlea of cancer patients by neutralizing the ototoxic chemotherapy drug cisplatin, Cobb says, while “most of the rest of our pipeline at the moment is gene therapeutics.”

Those gene therapy programs—Decibel is looking at both congenital monogenic deafness and vestibular disorders—are in preclinical stages of development, but the company has been able to identify multiple targets through a partnership with Regeneron, according to Cobb.

The monogenic hearing loss program is the most advanced, according to Jonathon Whitton, a pediatric audiologist who is spearheading that work. “Many of these cases are being driven by a mutation in a single gene,” he says, “so they’re essentially not making a specific protein that’s important for running the machinery in the inner ear.” Decibel hopes to deliver those proteins—which have not yet been disclosed—and restore hearing function.

At the clinical level, the DB-020 treatment to prevent cisplatin toxicity- mediated hearing loss is moving into a Phase Ib trial in coming months, Cobb says, while their DB-041 program will attempt to prevent hearing loss due to the ototoxicity of amino glycoside antibiotics. The only drug in the Decibel pipeline that is systemically delivered, the DB-041 program lags slightly behind DB-20, she says. “We’re still going through the Phase I data and trying to identify whether it supports moving forward into Phase II.”

The Decibel approach is broad, following multiple leads under the belief that the otology space is fundamentally going to change, notes Cobb, with many companies delivering life-changing treatments. “We’re investing based on our anticipation of what that space will be,” she adds. “We want to be the dominant player in the space.”

 

Using an orally administered systemic treatment

Seattle’s Sound Pharmaceuticals approach is more focused than Decibel or Otonomy, at least in terms of potential treatments. Rather than developing new techniques for delivering therapies locally, Sound Pharma is going with an orally administered systemic treatment, according to founder and CEO, Jonathan Kil, MD, PhD. Sound Pharma is advancing a propriety small molecule, Ebselen/SPI-1005, as a potential answer to everything from hearing loss from ototoxic drugs like cisplatin to Ménière’s disease to even, perhaps, some neuropsychiatric indications.

“Ebselen is a glutathione peroxidase-1 mimic and inducer, and “GPX, as we abbreviate it, especially GPX-1, is dominant in the cochlea,” being highly expressed in hair cells, Kil says. A part of the anti-inflammatory response, GPX is thought to be involved in cellular repair mechanisms, he says, and GPX-1 knockout mice are more sensitive to injury by noise and ototoxic drugs. Sound Pharma is betting that Ebselen can help prevent and perhaps even reverse such damage.

cochleae explant cultures
Representative images of cochleae explant cultures show that ebselen reduced tobramycin-induced ototoxicity. A) Control cochleae have undamaged rows of hair cells (untreated). B) Ebselen treatment alone did not result in damage. C) Tobramycin treatment alone caused significant damage to the cochlea, resulting in a smaller undamaged region D) Ebselen treatment reduced AG-induced damage to the cochlea, resulting in a larger undamaged region Scale bar = 50 µm. [Sound Pharma]
A Phase II trial for mild to moderate voice induced hearing loss showed promise in humans and led to a 2017 paper in The Lancet,1 while in animal models Ebselen significantly reduced hair cell loss due to noise and cisplatin damage. The company has also completed Phase Ib and Phase IIb trials for use of Ebselen in treating Ménière’s, leading to Ebselen being awarded fast track status by the FDA.

Sound Pharma is also poised to release results from another Phase II trial involving Ebselen that could see the company branch out. The trial has been a collaboration with researchers at the University of Oxford, who believe Ebselen could be an effective treatment for people with bipolar disorder, according to Kil. “GPX-1 is highly expressed in prefrontal cortex of brain where a lot of cognitive behavioral changes have been demonstrated,” he points out. “It’s very interesting to see where science will take you.”

 

Trail blazing … and the occasional backtracking

There are a lot of promising paths and approaches in such a new space. Not all of them will work out. Autifony, based in the U.K, had pinned their hopes on AUT00063, a drug that inhibited the activity of Kv3 potassium ion channels in the auditory system, taking the drug through Phase II clinical trials for hearing loss, age related hearing loss, and tinnitus. But according to CBO Barbara Domayne-Hayman, DPhil, the trials failed due to a lack of efficacy. They think AUT00063 was the wrong molecule and lacked sufficient potency, she says, though Autifony still believes that “the Kv3 mechanism has strong potential in hearing disorders.”

 

 Many ways to get somewhere

Audion CEO Rolf Jan Rutten is well aware of the uncertainties in a burgeoning field like treating hearing loss, but he remains optimistic about progress in the field. “It’s difficult to predict who will be successful, but let’s hope for the sake of the patients that somebody will be,” he says.

Based in the Netherlands but with labs in Cambridge, MA, Audion is focused on Mikulec’s “holy grail,” regenerating lost hair cells in the cochlea. Their candidate to do this is LY3056480, a gamma-secretase inhibitor licensed from Eli-Lilly, an approach based on a 2013 paper in Neuron that showed LY3056480 was able to regenerate lost hair cells in mice.2
The cochlea contains four rows of hair cells separated by support cells, a pattern ensured by lateral inhibition mediated by Notch—a gene involved in determining cell fates—signaling during development.  LY3056480 may inhibit Notch signaling, which in mice models lead to support cells differentiating into new hair cells.

Audion has now completed a Phase I clinical trial for LY3056480 in humans with mild, adult onset hearing loss and are recruiting for a Phase II trial.

But Jan Rutten is adamant that he is far from declaring Audion anywhere close to a eureka moment just yet. “Before you hear me claim such a thing, I think it is really important to do the clinical research,” he says. “I think the biggest disservice that we can do to the field is to project unrealistic expectations,” he says. There’s a lot of good scientists at a lot of different companies doing the work, and “hopefully we’ll come up with something.”

Mikulec, certainly, sees progress in the field as the next step in the evolution of treating diseases of the ear. In the pre-antibiotics era of the 1930s and 1940s, doctors repaired ruptured eardrums and removed the mastoid, the bony area behind the ear, to control ear infections. In the 1950s, 1960s, and 1970s, otolaryngologists dealt with cholesteatoma, cysts that form in children’s ears when their eustachian tubes aren’t functioning properly. The 1970s and 1980s brought the cochlear implant. Now the era of regular inner ear interventions may have arrived.

“When I entered the field of inner ear drug delivery as my research focus, it was kind of a niche field, a few guys playing with rodents in a corner,” Mikulec says. “The science has really taken off, and certainly the interest from startups has taken off.”

 

References
1. Kil, Jonathan, et al. “Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomized, double-blind, placebo-controlled phase 2 trial.” The Lancet. Vol 390, Issue 10098, p 969-979.
2. Mizutari, Kunio, et al. “Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma.” Neuron. Volume 77, Issue 1, p 58-69.

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